Methicillin-resistant Staphylococcus aureus Bacterial Nitric-oxide Synthase Affects Antibiotic Sensitivity and Skin Abscess Development

Sorge, Nina M. van; Beasley, Federico C.; Gusarov, Ivan; Gonzalez, David J.; Köckritz-Blickwede, Maren von; Anik, Sabina; Borkowski, Andrew W.; Dorrestein, Pieter C.; Nudler, Evgeny; Nizet, Victor

doi:10.1074/jbc.m112.448738

Cited by 93 publications

(124 citation statements)

References 67 publications

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“…Conclusion-Between a series of recent gene knock-out experiments and subsequent biological assays, it is clear that bNOS functions in pathogenic bacteria to provide a protective barrier against reactive oxygen species and a variety of antibiotics (7,8,43,44). Therefore, by inhibiting the enzymatic function of bNOS, it is plausible that we can improve the efficacy of antibiotic treatments targeting pathogenic bacteria such as S. aureus and B. anthracis.…”

Section: Resultsmentioning

confidence: 99%

Identification of Redox Partners and Development of a Novel Chimeric Bacterial Nitric Oxide Synthase for Structure Activity Analyses

Holden

Lim

Poulos

2014

Journal of Biological Chemistry

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Background: Inhibition of bacterial nitric oxide synthase (NOS) improves the efficacy of antibiotics. Results: Development and characterization of a novel bacterial NOS chimera supports NO production in the presence of NADPH and a flavodoxin reductase. Conclusion: Structure activity relationship between NOS inhibitors and bacterial NOS can now be evaluated. Significance: Assays can be adapted for high-throughput screening to identify new bacterial NOS inhibitors.

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Section: Resultsmentioning

confidence: 99%

Identification of Redox Partners and Development of a Novel Chimeric Bacterial Nitric Oxide Synthase for Structure Activity Analyses

Holden

Lim

Poulos

2014

Journal of Biological Chemistry

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“…Strategies to prevent H 2 O 2 depletion may therefore improve infection outcomes. For example, the recent development of specific bacterial nitric oxide synthase (bNOS) inhibitors (48a) to counter S. aureus expression of bNOS that promotes ROS resistance (120a) opens up new antimicrobial possibilities.…”

Section: Resistance To Host Oxidative Burst Killingmentioning

confidence: 99%

Subterfuge and Sabotage: Evasion of Host Innate Defenses by Invasive Gram-Positive Bacterial Pathogens

Okumura

Nizet

2014

Annu. Rev. Microbiol.

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The development of a severe invasive bacterial infection in an otherwise healthy individual is one of the most striking and fascinating aspects of human medicine. A small cadre of gram-positive pathogens of the genera Streptococcus and Staphylococcus stand out for their unique invasive disease potential and sophisticated ability to counteract the multifaceted components of human innate defense. This review illustrates how these leading human disease agents evade host complement deposition and activation, impede phagocyte recruitment and activation, resist the microbicidal activities of host antimicrobial peptides and reactive oxygen species, escape neutrophil extracellular traps, and promote and accelerate phagocyte cell death through the action of pore-forming cytolysins. Understanding the molecular basis of bacterial innate immune resistance can open new avenues for therapeutic intervention geared to disabling specific virulence factors and resensitizing the pathogen to host innate immune clearance.

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“…[147][148][149] The S. aureus nitric oxide synthase also protects against killing by neutrophils, as well as being involved in the development of skin abscesses in a mouse model. [150][151][152] Staphylococcus aureus is tolerant to nitrosative stress by transcriptional reprogramming that involves at least 84 identified genes, many of which have roles in iron-homeostasis and hypoxic metabolism; the latter falling under the influence of the indirect O 2 -responsive SrrAB two-component system (see above). Consequently, an srrAB mutant exhibited enhanced sensitivity to NO and this was partially attributed to dysregulation of the NO detoxification enzyme Hmp (see above), but the divergently transcribed ldh1 gene, encoding lactate dehydrogenase was subsequently shown to be essential for virulence and maintaining redox balance during nitrosative stress.…”

Section: Nitric Oxide Responsesmentioning

confidence: 99%

Transcriptional regulation of bacterial virulence gene expression by molecular oxygen and nitric oxide

2014

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Molecular oxygen (O 2 ) and nitric oxide (NO) are diatomic gases that play major roles in infection. The host innate immune system generates reactive oxygen species and NO as bacteriocidal agents and both require O 2 for their production. Furthermore, the ability to adapt to changes in O 2 availability is crucial for many bacterial pathogens, as many niches within a host are hypoxic. Pathogenic bacteria have evolved transcriptional regulatory systems that perceive these gases and respond by reprogramming gene expression. Direct sensors possess iron-containing co-factors (iron-sulfur clusters, mononuclear iron, heme) or reactive cysteine thiols that react with O 2 and/or NO. Indirect sensors perceive the physiological effects of O 2 starvation. Thus, O 2 and NO act as environmental cues that trigger the coordinated expression of virulence genes and metabolic adaptations necessary for survival within a host. Here, the mechanisms of signal perception by key O 2 -and NO-responsive bacterial transcription factors and the effects on virulence gene expression are reviewed, followed by consideration of these aspects of gene regulation in two major pathogens, Staphylococcus aureus and Mycobacterium tuberculosis.

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Methicillin-resistant Staphylococcus aureus Bacterial Nitric-oxide Synthase Affects Antibiotic Sensitivity and Skin Abscess Development

Cited by 93 publications

References 67 publications

Identification of Redox Partners and Development of a Novel Chimeric Bacterial Nitric Oxide Synthase for Structure Activity Analyses

Identification of Redox Partners and Development of a Novel Chimeric Bacterial Nitric Oxide Synthase for Structure Activity Analyses

Subterfuge and Sabotage: Evasion of Host Innate Defenses by Invasive Gram-Positive Bacterial Pathogens

Transcriptional regulation of bacterial virulence gene expression by molecular oxygen and nitric oxide

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